The invention relates to piperidine derivatives as N-Methyl-D-Aspartate (NMDA) antagonists useful in the treatment of diseases and disorders responsive to antagonism of NMDA receptors.
Many of the physiological and pathophysiological effects of the endogenous excitatory neurotransmitter glutamate are mediated via actions at N-Methyl-D-Asparate (NMDA) receptors. Over-excitation of the NMDA receptors on postsynaptic cells-mediated by excessive release of glutamate from nerve endings or glial cells-results in a massive calcium ion influx through a calcium ion channel into neuronal cells, leading to neuronal cell death. These events occur under ischemic or hypoxic conditions such as, for example, stroke, hypoglycemia, cardiac arrest, or acute physical trauma.
NMDA receptors in vivo form an NMDA receptor channel complex in cell walls comprising at least three binding domains, including a glutamic acid (or NMDA) recognition site, a channel blocking binding site, and a strychnine-insensitive glycine binding site. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor, thereby preventing calcium ion influx into cells. Accordingly, an NMDA receptor antagonist is therapeutically useful because it minimizes damage to the central nervous system induced by calcium ion influx under ischemic or hypoxic conditions.
A functional NMDA receptor is comprised of the combination of at least one subunit termed xe2x80x9cNR1xe2x80x9d, which has 8 splice variants including NR1A, and one (or more) subunit termed xe2x80x9cNR2Axe2x80x9d, xe2x80x9cNR2Bxe2x80x9d, xe2x80x9cNR2Cxe2x80x9d, and xe2x80x9cNR2Dxe2x80x9d. The combinations are designated NR1/2A, NR1/2B, NR1/2C and NR1/2D, respectively. The different NR2 subunits have distinct developmental and anatomical distributions. This suggests that agents that selectively antagonize one NR1/NR2 combination would have therapeutic actions without the psychotomimetic or dysphoric side effects associated with antagonists which block multiple NR1/NR2 combinations.
A subtype-selective NMDA receptor antagonist may be identified by methods well known in the pharmaceutical arts, such as, for example, screening compounds in an electrophysiology assay. In one such electrophysiology assay, different subunit combinations of recombinant NR1 and NR2 receptors are expressed in Xenopus oocytes, and a potential agent is administered at different concentrations. NMDA-based electrical currents are activated by co-administration of fixed concentrations of an excitatory amino acid such as, for example, glutamic acid or glycine. The ability of an agent to antagonize the activation of the electrical current by an excitatory amino acid is measured by recording the change in the current versus the change in the concentration of the agent.
Screening of compounds in recent years have identified a number of NMDA receptor antagonists that have been used in animal and clinical human studies to demonstrate proof of concept for use of such an antagonist in the treatment of a variety of disorders. Disorders known to be responsive to blockade of NMDA receptors include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, pain, including chronic and neuropathic pain, anxiety, and chronic neurodegenerative disorders such as Parkinson""s disease. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control symptoms of withdrawal from addictive drugs. In fact, excessive excitation by neurotransmitters may be responsible for the loss of neurons in a wide variety of conditions. Additional conditions include cerebral vascular disorders such as cerebral ischemia or cerebral infarction resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such as from near drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer""s disease, and Huntington""s disease. Other conditions amendable to treatment with an subtype-selective NMDA receptor antagonist include amyotrophic lateral sclerosis (ALS), epilepsy, and schizophrenia.
For example, studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial pharmacological effects on patients suffering from Parkinson""s disease. In Parkinson""s disease, there is a loss of dopamine neurons in the substantia nigra. Secondary to this dopamine loss is a hyperactivity of specific brain glutamatergic pathways. This glutamatergic hyperactivity is thought to mediate some of the pathophysiological aspects of Parkinson""s disease, as well as some of the side effects associated with the long term treatment of the disease by dopamine agonists, such as L-DOPA, pergolide, ropinirole or pramipexole. Clinical studies in humans have demonstrated that antagonists at NMDA receptors have beneficial effects in Parkinson""s disease or in treating the side effects associated with the treatment of Parkinson""s disease with dopamine agonists.
Pain is another example of a condition shown to be responsive to NMDA receptor antagonism. For example in previous studies, stimulation of NMDA receptors by afferent nerves transmitting painful stimuli has been demonstrated to be involved in hyperalgesic and neuropathic pain states. Animal studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial effects in treating hyperalgesic and neuropathic pain states.
However, while NMDA antagonists have been successfully used to demonstrate the proof of concept mentioned above, very few, if any, of these antagonists have shown a suitable drug profile in clinical studies. This is so even though numerous NMDA receptor antagonists have been synthesized and tested. For example, U.S. Pat. Nos. 5,714,502; 6,124,317; 6,124,323; and 6,130,234 describes the piperidine-based NMDA receptor antagonists shown below.
U.S. Pat. No. 5,714,502 provides piperidines of formula 
in which
R1 and R2 in each case independently of one another are unsubstituted or mono- to disubstituted phenyl radicals whose substituents can be A, OA, aryloxy having 6 to 10 C atoms, aralkyloxy having 7 to 11 C atoms, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94(bonded in directly adjacent positions or in the meta- or para-position to one another on the phenyl ring), xe2x80x94Oxe2x80x94(CH2)nxe2x80x94OH, Hal, CF3, OH, NO2, NH2, NHA, NA2, NHR3, NAR3, SO2NH2, SO2NHA, SO2NA2, SO2NHR3 (excluding R3xe2x95x90SO2A), SO2N(R3)2 (excluding R3xe2x95x90SO2A) or R3,
R3 is COH, CO-alkyl having 1 to 7 C atoms in the alkyl portion, CO-alkyl-aryl having 8 to 12 C atoms in the alkyl and aryl portions, CO-aryl having 7 to 13 C atoms in the aryl portion, or SO2A
A is an alkyl radical having 1 to 6 C atoms
n is 1 or 2
Hal is F, Cl, Br, or I,
and their physiologically acceptable salts. The invention also relates to the preparation of these novel compounds and their use as psychopharmacologically active substances.
U.S. Pat. No. 6,124,317 provides 2-substituted piperidine NMDA receptor antagonists of formula 
or a pharmaceutically acceptable salt thereof wherein
Ar1 and Ar2 are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, a halogenated alkyl group, halogen, nitro, aryl, aralkyl, amino, a lower alkyl amino group or a lower alkoxy group;
each R1 is independently hydrogen, alkyl or hydroxy;
each R2 is independently hydrogen, alkyl or hydroxy;
X is xe2x80x94CH2xe2x80x94, O, S, or NR3, wherein R3 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;
Y is xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, O, S or NR3;
m is 0, 1 or 2; and
n is 0, 1, 2, 3, 4 or 5,
provided that when m is 0 and X is xe2x80x94CH2xe2x80x94, or m is 1, R1 is H and X is xe2x80x94CH2xe2x80x94 that either Y is not xe2x80x94CH2xe2x80x94 or at least one of R2 is not hydrogen and further provided that when Y is xe2x80x94Cxe2x95x90Cxe2x80x94 then X is not O.
U.S. Pat. No. 6,124,323 provides 4-substituted piperidine-based NMDA receptor antagonists of formula 
or a pharmaceutically acceptable salt thereof wherein
Ar1 and Ar2 are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, aldehyde oxime, lower alkoxy carbonylmethyl, hydroxy lower alkyl, amino carbonylmethyl, hydrazinocarbonylmethyl, acetamido, aryl, aralkyl, amino, a halogenated alkyl group, a lower alkyl amino group or a lower alkoxy group;
z is a single or double bond;
X is xe2x80x94(CHR3)mxe2x80x94, O, S or NR4, wherein each R3 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms, R4 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, provided that when z is a double bond then X is not O or NR4;
R1 is hydrogen or hydroxy;
each R2 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms;
n is 0, 1, 2, 3 or 4;
Y is O, S, NR4 or a single bond; and
R5 is hydrogen or hydroxy when z is a single bond preferably provided that:
(i) R2 cannot be hydroxy in a position alpha to Ar2; (ii) if X is a single bond, z is a double bond or R5 is hydroxy and Ar2 is phenyl then Y cannot be O; (iii) if Y is O, n is 3 or 4, R2 is exclusively hydrogen, z is a single bond, R1 and R5 are hydrogen and Ar2 is phenyl, or halogen, methoxy, or trifluoromethyl substituted phenyl then X cannot be methylene or ethylene; (iv) if X is xe2x80x94(CHR3)mxe2x80x94, m is 2 and R3 is exclusively hydrogen then Ar1 cannot be imidazolyl substituted; (v) if Y is O, n is 2, 3 or 4, R2 is hydrogen or hydroxy, z is a single bond, R1 and R5 are hydrogen, and Ar2 is phenyl, or NO2, CN, 1-imidazoyl, or 1,2,4-triazol-1-yl substituted phenyl then X cannot be methylene, hydroxymethylene, or O; (vi) if Y is O or S, R1 and R5 are hydrogen and R2 is hydroxy then X is not methylene or a single bond; or (vii) if Y is a single bond, R2 is exclusively hydrogen and Ar2 is phenyl, then either R1 or R5 must be hydroxy.
U.S. Pat. No. 6,130,234 provides piperidine-based NMDA receptor antagonists of formula 
or a pharmaceutically acceptable salt thereof wherein
Ar1 and Ar2 are independently aryl or a heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, xe2x80x94NHAc, xe2x80x94NHSO2Me, xe2x80x94N(SO2Me)2, xe2x80x94CONHalkyl, xe2x80x94SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group;
z is a single or double bond;
X is xe2x80x94(CHR2)mxe2x80x94, O, S or NR3, wherein each R2 is independently hydrogen, hydroxy, lower alkoxy or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, and R3 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, provided that when z is a double bond then X is not O, S or NR3;
R1 is hydrogen or hydroxy;
n is 0, 1 or 2;
Q is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94; and
R4 is hydrogen or hydroxy when z is a single bond provided that: (i) when n is 0, then z is a double bond and R4 is not present; (ii) when n is 1 or 2 and Q is xe2x80x94Cxe2x89xa1Cxe2x80x94 and z is a double bond or R4 is hydroxy, then Ar1 is aryl substituted by halogen; and (iii) when R4 is hydroxy then R2 is not hydroxy or lower alkoxy.
The difficulty referenced above with demonstrating clinical utility of NMDA receptor antagonists has been the antagonists"" lack of NMDA receptor subtype selectivity and/or biological activity when dosed orally. Before the present invention, many of the drugs of the NMDA receptor antagonist class were nonselective antagonists of NMDA receptor subtypes that were administered intravenously (IV), which accounts for their undesired side effects and lack of efficacy, respectively. Given that the need for medicinal agents that treat diseases responsive to antagonism of NMDA receptors remains unmet, the search for NMDA receptor antagonists that are subtype-selective and orally efficacious continues.
A series of novel piperidines have been discovered that are subtype-selective NMDA receptor antagonists and are efficacious in vivo when dosed orally. All that is needed to practice the invention is to administer from 1 to 6 times daily to a patient in need thereof, a therapeutically effective amount of a compound of the invention. As is discussed below, determination of dosage forms and amounts of the invention compounds, routes of administration, and identification of patients in need of treatment, is within the average skill in the pharmaceutical and medical arts.
Described are piperidines of Formula I 
and pharmaceutically acceptable salts thereof wherein:
R1 is independently selected from alky, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkylaminoalkyl, hydroxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, carboxyalkyl, haloalkyl, and halogen;
g is an integer of from 0 to 3;
Z is (CH2)h, Cxe2x95x90O, O, S, SO, SO2, CHOH, or C(Me)OH;
h is an integer of from 0 or 1;
R2 is hydrogen, OH, alkoxy, or substituted alkoxy;
R3 is hydrogen, OH, alkoxy, or substituted alkoxy;
V is (CH2)n or (CH2)mxe2x80x94Cxe2x95x90O, wherein n is an integer of from 1 to 4, and m is an integer of from 0 to 4;
B is a 4-, 5-, or 6-membered, carbon-linked, substituted or unsubstituted, heterocyclene, containing from 1 to 3 heteroatoms, which are N, O, or S, selected from the group consisting of:
(i) 1-aza-2-cyclobutanon-3,4-diyl of formula 
(ii) a 5-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro diradical heterocyclic ring having carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S;
(iii) a 5-membered oxo-substituted, nonaromatic tetrahydro, diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms selected from N, O, and S;
(iv) a 6-membered aromatic, nonaromatic tetrahydro, or nonaromatic hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms, which heteroatoms are nitrogen, and
(v) a 6-membered nonaromatic oxo-substituted hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms which are nitrogen and 0 or 1 heteroatom which is oxygen
wherein the atoms of the heterocyclene ring that are bonded to the group V and the phenyl bearing the group (X1)d are carbon atoms, and further wherein when B is a nonaromatic heterocycle containing sulfur, said sulfur may further comprise 
X1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aralkyl, substituted aralkyl, halogen, haloalkyl, cyano, nitro, amino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl, carboxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, or C(O)-alkyl;
d is an integer of from 0 to 2;
E is hydrogen; and
Y is OH; or
E and Y may be taken together with the phenylene to which they are attached to form a fused 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms in E to Y selected from N, O, and S, wherein
E is a linker group containing 2 or 3 atoms of the bicyclic ring, and
Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring.
Preferred is a compound of Formula I wherein:
B is a heterocyclene selected from the group consisting of: 
xe2x80x83wherein X is selected from O, S, and Nxe2x80x94R, wherein R is hydrogen or alkyl;
X1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aralkyl, halogen, haloalkyl, cyano, nitro, amino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl, carboxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, or C(O)CH3, and one X1 is ortho to V and para to E; and
R2 is hydrogen or OH;
R3 is hydrogen or OH;
V is CH2 or Cxe2x95x90O;
Z is (CH2)h; and
h is 1.
Preferred is a compound of Formula II 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, B, X1, and d are as defmed above for Formula I; and wherein when B is a 5-membered, oxo-substituted, nonaromatic tetrahydro, diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms selected from N, O, and S which is an oxazolidinone, the oxazolidinone is selected from: 
Also preferred is a compound of Formula III 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, B, X1, and d are as defined above for Formula I; and
E and Y together with the phenylene to which they are attached form a 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms selected from N, O, and S wherein
E is a linker group containing 2 or 3 atoms of the bicyclic ring; and
Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring.
More preferred is a compound of Formula III wherein
Y is selected from xe2x80x94N(H)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, and xe2x80x94N(OH)xe2x80x94, and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94C(O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94Nxe2x95x90C(H)xe2x80x94, xe2x80x94N(H)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94; or
Y is selected from xe2x95x90C(OH)xe2x80x94; and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94Nxe2x95x90, xe2x80x94Oxe2x80x94Nxe2x95x90, xe2x80x94Sxe2x80x94Nxe2x95x90, xe2x80x94C(O)xe2x80x94N(H)xe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90.
More preferred is a compound of Formula III wherein:
xe2x80x94Exe2x80x94Yxe2x80x94 is selected from the group consisting of
xe2x80x94CHxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94C(H)xe2x95x90C(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Sxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(OH)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90C(OH)xe2x80x94,
xe2x80x94(CH2)3xe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94.
Also preferred is a compound of Formula IV 
and pharmaceutically acceptable salts thereof wherein R1, g, h, R2, V, B, X1, and d are as defined above for Formula I; and
X2 is selected from O, S, NH, and CH2; and
B is selected from the group consisting of: 
wherein X is selected from O, S, and Nxe2x80x94R, wherein R is hydrogen or alkyl, and wherein Z is selected from O or S.
More preferred is a compound of Formula IV selected from the group consisting of:
6-[5-(4-Benzylpiperidin-1-ylmethyl)-4,5-dihydroisoxazol-3-yl]-3H-benzoxazol-2-one;
6-[5-(4-Benzylpiperidin-1-ylmethyl)-3-methylisoxazol-4-yl]-3H-benzoxazol-2-one;
6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one hydrochloride;
(+)-6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
(xe2x88x92)-6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-{3-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-5-yl}-3H-benzoxazol-2-one;
6-{2-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]thiazol-5-yl}-3H-benzoxazol-2-one;
6-{2-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]thiazol-5-yl}-3H-benzothiazol-2-one;
5-[2-(4-Benzylpiperidin-1-ylmethyl)thiazol-5-yl]-1,3-dihydrobenzimidazole-2-thione;
6-{2-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]oxazol-5-yl}-3H-benzothiazol-2-one;
6-[2-(4-Benzylpiperidin-1-ylmethyl)oxazol-5-yl]-3H-benzoxazol-2-one;
5-[2-(4-Benzylpiperidin-1-ylmethyl)oxazol-5-yl]-1,3-dihydroindol-2-one;
6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydrothiazol-2-yl}-3H-benzoxazol-2-one;
6-[5-(4-Benzylpiperidin-1-ylmethyl)-4,5-dihydrothiazol-2-yl]-3H-benzoxazol-2-one;
6-[2-(4-Benzylpiperidin-1-ylmethyl)-4,5-dihydrothiazol-5-yl]-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]isoxazol-3-yl}-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzyl)piperidin-1-yl]methyl}-4,5-dihydroisoxazol-3-yl}-3H-benzothiazol-2-one;
6-[5-(4-Benzyl-4-hydroxypiperidin-1-ylmethyl)-4,5-dihydroisoxazol-3-yl]-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzyl)piperidine-1-carbonyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-(5-{2-[4-(4-Fluorobenzyl)piperidin-1-yl]ethyl}-4,5-dihydroisoxazol-3-yl)-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzyl)-4-hydroxypiperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-5-methyl-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid;
5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid methyl ester;
4-(4-Fluorobenzyl)-1-[3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazol-5-ylmethyl]piperidine-4-carboxylic acid ethyl ester;
4-(4-Fluorobenzyl)-1-[3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazol-5-ylmethyl]piperidine-4-carboxylic acid;
6-{5-[4-(4-Fluorobenzyl)-3-hydroxypiperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl }-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorophenoxy)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorophenylsulfanyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzenesulfinyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-{5-[4-(4-Fluorobenzoyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-(5-{4-[(4-Fluorophenyl)hydroxymethyl]piperidin-1-ylmethyl}-4,5-dihydroisoxazol-3-yl)-3H-benzoxazol-2-one;
4-Chloro-6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-5-methyl-3H-benzoxazol-2-one;
-{5-[4-(4-Fluorophenyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-2-one;
6-[5-(4-Phenyl-4-hydroxy)piperidin-1-ylmethyl)-4,5-dihydroisoxazol-3-yl]-3H-benzoxazol-2-one; and
6-(5-{2-[4-(4-Fluorophenyl)piperidin-1-yl]ethyl }-4,5-dihydroisoxazol-3-yl)-3H-benzoxazol-2-one.
More preferred is a compound of Formula IV named (xe2x88x92)-6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one.
Still more preferred is a compound of Formula IV named (+)-6-{5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one.
Preferred is a compound of Formula V 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
Preferred is a compound of Formula VI 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
Preferred is a compound of Formula VII 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I; and
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl.
Preferred is a compound of Formula VIII 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I; and
X is O, S, or Nxe2x80x94R, wherein R is independently hydrogen or alkyl.
Preferred is a compound of Formula IX 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I; and
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl.
Preferred is a compound of Formula X 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
Preferred is a compound of Formula XI 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
X is O, S, or Nxe2x80x94R, wherein R is hydrogen or alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
Preferred is a compound of Formula XII 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I.
Preferred is a compound of Formula XIII 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I.
Preferred is a compound of Formula XIV 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
R is hydrogen or alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
Preferred is a compound of Formula XV 
and pharmaceutically acceptable salts thereof wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above for Formula I;
R is hydrogen, alkyl, or substituted alkyl; and
* means a chiral center designated R, S, or mixtures thereof.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a diluent, carrier, or excipient.
In a preferred embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II or Formula IV together with a diluent, carrier, or excipient.
In a more preferred embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of:
(+)-6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one;
(xe2x88x92)-6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one, or
a pharmaceutically acceptable salt thereof., together with a diluent, carrier, or excipient.
The invention also provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disorders are selected from stroke, cerebral ischemia, central nervous system disorders, depression, trauma, hypoglycemia, neurodegenerative disorders, anxiety, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, pain, including chronic pain, neuropathic pain, or surgical pain, and urinary incontinence.
In a more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disorder is pain.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disorder is Parkinson""s disease.
In a still more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula II or Formula IV.
In a still more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound selected from the group consisting of:
(+)-6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one;
(xe2x88x92)-6-{5-[4-(4-Fluorobenzyl)piperidin-1-ylmethyl]-4,5-dihydroisoxazol-3-yl}-3H-benzoxazol-3-one, or
a pharmaceutically acceptable salt thereof.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist wherein said dopamine agonist is L-DOPA.
In another preferred embodiment, the invention provides a method of treating disorders comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof in unit dosage form.
Also, the invention provides a compound selected from the group consisting of:
6-(2-Azido-1-hydroxyethyl)-3H-benzoxazol-2-one;
6-[2-Azido-1-(tert-butyldimethylsilanyloxy)ethyl]-3H-benzoxazol-2-one;
6-[2-Amino-1-(tert-butyldimethylsilanyloxy)ethyl]-3H-benzoxazol-2-one;
2-(4-Benzylpiperidin-1-yl)-N-[2-(tert-butyldimethylsilanyloxy)-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]acetamide;
2-(4-Benzylpiperidin-1-yl)-N-[2-(tert-butyldimethylsilanyloxy)-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]thioacetamide;
2-(4-Benzylpiperidin-1-yl)-N-[2-hydroxy-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]thioacetamide;
1-Chloro-3-[4-(4-fluorobenzyl)piperidin-1-yl]propan-2-ol;
1-Chloro-3-(4-benzylpiperidin-1-yl)propan-2-ol;
2-{3-[4-(4-Fluorobenzyl)piperidin-1-yl]-2-hydroxypropyl}isoindole-1,3-dione;
2-[3-(4-Benzylpiperidin-1-yl)-2-hydroxypropyl]isoindole-1,3-dione;
1-Amino-3-[4-(4-fluorobenzyl)piperidin-1-yl]propan-2-ol bis-hydrochloride salt;
1-Amino-3-[4-benzylpiperidin-1-yl]propan-2-ol bis-hydrochloride salt;
{3-[4-(4-Fluorobenzyl)piperidin-1-yl]-2-hydroxypropyl}carbamic acid benzyl ester;
[3-(4-Benzylpiperidin-1-yl)-2-hydroxypropyl]carbamic acid benzyl ester;
{2-(tert-Butyldimethylsilanyloxy)-3-[4-(4-fluorobenzyl)piperidin-1-yl]propyl}carbamic acid benzyl ester;
{2-(tert-Butyldimethylsilanyloxy)-3-[4-benzylpiperidin-1-yl]propyl}carbamic acid benzyl ester;
{2-(tert-Butyldimethylsilanyloxy)-3-[4-(4-fluorobenzyl)piperidin-1-yl]propylamine;
Methyl 2-oxo-2,3-dihydrobenzoxazole-6-carboxylate;
2-Oxo-2,3-dihydrobenzoxazole-6-carboxylic acid;
2-Oxo-2,3-dihydrobenzoxazole-6-carboxylic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide;
2-Oxo-2,3-dihydrobenzoxazole-6-carboxylic acid [3-(4-(4-fluorobenzyl)piperidin-1-yl)-2-(tert-butylimethylsilanyloxy)propyl]amide;
2-Oxo-2,3-dihydrobenzoxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide;
2-Oxo-2,3-dihydrobenzooxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]amide;
6-(2-Azido-1-hydroxyethyl)-3H-benzoxazol-2-one;
6-[2-Azido-1-(tert-butyldimethylsilanyloxy)ethyl]-3H-benzoxazol-2-one;
6-[2-Amino-1-(tert-butyldimethylsilanyloxy)ethyl]-3H-benzoxazol-2-one;
2-(4-Benzylpiperidin-1-yl)-N-[2-(tert-butyldimethylsilanyloxy)-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]acetamide;
2-(4-Benzylpiperidin-1-yl)-N-[2-(tert-butyldimethylsilanyloxy)-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]thioacetamide; and
2-(4-Benzylpiperidin-1-yl)-N-[2-hydroxy-2-(2-oxo-2,3-dihydrobenzoxazol-6-yl)ethyl]thioacetamide.
Also, the invention provides a process for preparing the compound of Formula I and pharmaceutically acceptable salts thereof comprising the steps of:
1) aminating a precursor alkyl halide;
2) cyclizing the product of Step 1;
3) recovering the desired compound of Formula I; and
4) converting, if desired, to a pharmaceutically acceptable salt.
Also, the invention provides a process for preparing the compound of Formula I and pharmaceutically acceptable salts thereof comprising the steps of:
1) halogenating an unsaturated side chain of a precursor to the compound;
2) cyclizing the product of Step. 1;
3) recovering the desired compound of Formula I; and
4) converting, if desired, to a pharmaceutically acceptable salt.
As recited above, one aspect of the present invention is a compound of Formula I 
and a pharmaceutically acceptable salt thereof, wherein R1, g, Z, h, R2, R3, V, B, X1, d, E, and Y are as defined above.
All of the references cited herein, including patents, are incorporated herein by reference.
The following definitions apply to terms used in this specification and claims.
The term xe2x80x9cpatientxe2x80x9d means a mammal, including a human.
Preferred patients are humans, cats, and dogs.
The term xe2x80x9cIC50xe2x80x9d means the concentration of test compound required to inhibit activity of a receptor or enzyme by 50%.
The term xe2x80x9cL-DOPAxe2x80x9d means 3-hydroxy-L-tyrosine.
The term xe2x80x9c(X1)dxe2x80x9d wherein d is an integer of from 0 to 2 means the group X1 is present 0 to 2 times on the phenylene to which it is attached. The groups X1 are independently the same or different. Illustrative examples of substituted phenylenes are drawn below.
d is 0: 
d is 1: 
d is 2: 
Likewise the term xe2x80x9c(R1)gxe2x80x9d wherein g is an integer of from 0 to 3 means the group R1 is present 0 to 3 times on the phenyl to which it is attached. The groups R1 are independently the same or different. Illustrative examples of substituted phenyls are drawn below.
g is 0: 
g is 1: 
g is 2: 
g is 3: 
The term xe2x80x9ccomprisingxe2x80x9d, which is synonymous with the terms xe2x80x9cincludingxe2x80x9d, xe2x80x9ccontainingxe2x80x9d, or xe2x80x9ccharacterized byxe2x80x9d, is inclusive or open-ended and does not exclude additional, unrecited elements or method steps from the scope of the invention that follows.
The phrase xe2x80x9cconsisting ofxe2x80x9d, is closed-ended and excludes any element, step, or ingredient not specified in the description of the invention that follows.
The phrase xe2x80x9cconsisting essentially ofxe2x80x9d limits the scope of the invention that follows to the specified elements or steps and those further elements or steps that do not materially affect the basic and novel characteristics of the invention.
The phrase xe2x80x9cfilter aidxe2x80x9d means a filter medium comprising small particulates. Illustrative examples of filter aids include kieselguhr and CELITE (Celite Corporation, Lompoc, Calif.), a diatomaceous earth filter aid.
The term xe2x80x9calkylxe2x80x9d means a straight or branched, unsubstituted or substituted, hydrocarbon group having from 1 to 12 carbon atoms. Preferred alkyl groups are C1-C6 alkyl. Typical examples of unsubstituted alkyl groups include methyl (i.e., CH3xe2x80x94), ethyl, 1-propyl, and 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 1-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 5-methyl-1-hexyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 6-methyl-1-heptyl, 5,5-dimethylhexyl, 1-nonyl, 2-nonyl, 1-decyl, 2-decyl, 1-undecyl, 2-undecyl, 1-dodecyl, and 5-dodecyl. Substituted alkyl groups are described below.
The term xe2x80x9calkenylxe2x80x9d means a straight or branched, unsubstituted or substituted, hydrocarbon group having from 2 to 12 carbon atoms and 1 or 2 sites of unsaturation. Preferred groups are C2-C6 alkenyl. Illustrative examples of unsubstituted alkenyl groups include ethenyl [i.e., CH2xe2x95x90C(H)xe2x80x94], 1-propenyl, 2-propenyl, 1-buten-1-yl, 2-buten-1-yl, 1-penten-1-yl, 2-penten-1-yl, 1-penten-3-yl, 1-penten-5-yl, 1-hexen-1-yl, 1-hexen-4-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-octen-3-yl, 5-nonen-2-yl, 4-undecen-4-yl, and 5-dodecen-2-yl. Substituted alkenyl groups are defined below.
The term xe2x80x9calkoxyxe2x80x9d means a straight or branched, substituted or unsubstituted, alkyl group of from 1 to 12 carbon atoms linked through an oxygen atom. Preferred is C1-C6 alkoxy. Illustrative examples of unsubstituted alkoxy groups include methoxy (i.e., CH3xe2x80x94Oxe2x80x94), ethoxy, isopropoxy, tert-butoxy, iso-pentoxy, octyloxy, and 7,7-dimethyloctyloxy. Substituted alkoxy groups are defined below.
The term xe2x80x9carylxe2x80x9d means an unsubstituted or substituted aromatic carbocyclic ring having 6 or 10 carbon atoms. Illustrative examples of unsubstituted aryl groups include phenyl (i.e., C6H5xe2x80x94), 1-naphthyl, and 2-naphthyl. Substituted aryl groups are defined below.
The term xe2x80x9caralkylxe2x80x9d means an unsubstituted or substituted aromatic carbocyclic ring having 6 or 10 carbon atoms (i.e., an aryl group) linked through an alkylene group, wherein alkylene is as defined below. Illustrative examples of unsubstituted aralkyl groups include benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 3-methyl-3-phenylpropyl, 1-naphthylmethyl, 1-naphthylethyl, 3-(1-naphthyl)-propyl, 4-(1-naphthyl)-butyl, 4-(2-naphthyl)-butyl, 4-phenylheptyl, and 12-(2-hydroxyphenyl)-dodec-3-yl. Substituted aralkyl groups are defined below.
The term xe2x80x9calkylenexe2x80x9d means a straight or branched hydrocarbon chain diradical of from 1 to 12 carbon atoms. Preferred groups are C1-C6 alkylene. Illustrative examples of alkylene groups include methylene (i.e., xe2x80x94CH2xe2x80x94), 1,2-ethylene, 1,2-propylene, 1,3-propylene, 2,2-dimethyl-hexane-1,6-diyl, and dodecan-1,12-diyl.
The term xe2x80x9ccycloalkylxe2x80x9d means an unsubstituted or substituted, saturated carbocyclic ring having from 3 to 7 carbon atoms. Illustrative examples of unsubstituted cycloalkyl groups include cyclopentyl, cyclopropyl, cyclohexyl or cycloheptyl. Substituted cycloalkyl is defined below.
As discussed above, the groups alkyl, alkenyl, alkoxy, aryl, aralkyl, and cycloalkyl may be substituted. These substituted groups are respectively termed: xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, xe2x80x9csubstituted alkoxyxe2x80x9d, xe2x80x9csubstituted arylxe2x80x9d, xe2x80x9csubstituted aralkylxe2x80x9d, and xe2x80x9csubstituted cycloalkylxe2x80x9d.
The groups can be substituted with from 1 to 3 substituents independently selected from halogen, OH, Oxe2x80x94(C1-C6 alkyl), OC(O)xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkylene)-OH, xe2x80x94(C1-C6 alkylene)-Oxe2x80x94(C1-C6 alkyl), NH2, N(H)xe2x80x94(C1C6 alkyl), Nxe2x80x94(C1-C6 alkyl)2, NHC(O)xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkylene)-NH2, xe2x80x94(C1-C6 alkylene)-N(H)xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkylene)-Nxe2x80x94(C1-C6 alkyl)2, SH, Sxe2x80x94(C1-C6 alkyl), Sxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C6 alkylene)-SH, xe2x80x94(C1-C6 alkylene)-Sxe2x80x94(C1-C6 alkyl), unsubstituted cycloalkyl, C(O)xe2x80x94(C1-C6 alkyl), CO2H, CO2xe2x80x94(C1-C6 alkyl), C(O)NH2, C(O)NHxe2x80x94(C1-C6 alkyl), and C(O)Nxe2x80x94(C1-C6 alkyl)2, wherein (C1-C6 alkyl) means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms, (C1-C6 alkylene) means a straight or branched hydrocarbon chain diradical of from 1 to 6 carbon atoms, and unsubstituted cycloalkyl is as defined above. Further, 1 of the 3 substituents in substituted alkyl, substituted alkenyl (on saturated carbons only), substituted alkoxy, substituted aralkyl (on saturated carbon atoms only) and substituted cycloalkyl may be oxo. Examples of these substituted groups are provided below.
Illustrative examples of substituted alkyl groups include HOCH2, CF3, (CH2)4SCH3, (CH2)8NH2, C(CH3)2CH[CO2C(CH3)3]CH3, CF2OH, and CH(CO2H)CH2CH2C(O)NMe2.
Illustrative examples of substituted alkenyl groups include 2-fluoro-ethen-1-yl [i.e., CH(F)xe2x95x90C(H)xe2x80x94], methyl propenoate-2-yl, and 5-iso-butoxy-1-penten-5-yl.
Illustrative examples of substituted alkoxy groups include fluoromethoxy (i.e., FCH2xe2x80x94Oxe2x80x94), 2-ethoxycarbonyl-ethoxy, 4-aminocarbonyl-oxybutyl, and 8-thio-nonyloxy [i.e., CH3CH(SH)xe2x80x94(CH2)7xe2x80x94Oxe2x80x94].
Illustrative examples of substituted aryl groups include 2-fluorophenyl, 2,4,6-trimethoxyphenyl, 4-chloro-2-methylphenyl, 5,6-dichloro-naphth-1-yl, and 8-(dimethylaminomethyl)-naphth-2-yl.
Illustrative examples of substituted aralkyl groups include 4-fluorophenylmethyl, 2-(2,4,6-trimethoxyphenyl)-ethyl, 3-(2-carboxyphenyl)-propyl, 4-phenyl-4-hydroxy-butyl, 4-(2-dimethylaminomethyl-naphth-1-yl)-butyl, and 12-(2-hydroxyphenyl)-dodec-3-yl.
Illustrative examples of substituted cycloalkyl groups include 3-methyl-cyclopentyl, 4-hydroxy-cyclohexyl, and 1-methoxy-cycloheptyl.
The term xe2x80x9cheteroatomxe2x80x9d includes nitrogen, oxygen, and sulfur. When the heteroatom is incorporated in a nonaromatic ring, the heteroatom further includes 
The term xe2x80x9coxoxe2x80x9d means xe2x95x90O.
The term xe2x80x9coxo-substitutedxe2x80x9d means any group which contains a carbon atom that is substituted with an oxo group (i.e., xe2x95x90O). A carbon atom substituted with an oxo group forms a carbonyl group of formula Cxe2x95x90O.
The phrase xe2x80x9cfused 9- or 10-membered bicyclic ring containing from 0 to 3 heteroatomsxe2x80x9d means a group wherein 2 ring systems share 2 and only 2 atoms. Illustrative examples of a fused bicyclic group containing 0 heteroatoms include 
The term xe2x80x9chalogenxe2x80x9d means bromine, chlorine, fluorine, or iodine.
The term xe2x80x9caminoalkylxe2x80x9d means a H2N group linked through an alkylene group, wherein alkylene has the meaning as defined above. Illustrative examples of aminoalkyl groups include aminomethyl (i.e., H2Nxe2x80x94CH2xe2x80x94), 3-aminopropyl, and 1-amino-1,1-dimethylethyl.
The term xe2x80x9calkylaminoalkylxe2x80x9d means an alkyl group, linked through an N(H) group, which in turn is linked through an alkylene group, wherein alkyl and alkylene are as defined above. Illustrative examples of alkylaminoalkyl groups include methylaminomethyl (i.e., CH3NHCH2xe2x80x94), 3-(tert-butylamino)-propyl, and 6-(hexylamino)-hexyl.
The term xe2x80x9chydroxyalkylxe2x80x9d means an OH group linked through an alkylene group, wherein alkylene has the meaning defined above. Illustrative examples of hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, and 2-hydroxy-1,1-dimethylethyl.
The term xe2x80x9c(aminocarbonyl)-alkylxe2x80x9d means an C(O)NH2 group linked through an alkylene group, wherein alkylene has the meaning defined above. Illustrative examples of (aminocarbonyl)-alkyl groups include H2NC(O)xe2x80x94CH2xe2x80x94 and H2NC(O)xe2x80x94C(CH3)3.
The term xe2x80x9c(alkylthio)-alkyl-xe2x80x9d means an alkyl group linked through a sulfur atom, which in turn is linked through an alkylene group, wherein alkyl and alkylene have the meanings defined above. Illustrative examples of (alkylthio)-alkyl groups include CH3xe2x80x94Sxe2x80x94CH2xe2x80x94, CH3CH2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, and CH3CH(CH3)CH2C(CH3)2xe2x80x94Sxe2x80x94C(CH3)2CH2xe2x80x94.
The term xe2x80x9ccarboxyalkylxe2x80x9d means a CO2H group linked through an alkylene group, wherein alkylene has the meaning defined above. Illustrative examples of carboxyalkyl groups include carboxymethyl, 2-carboxyethyl, and 2-carboxy-1,1-dimethylethyl.
The term xe2x80x9caminoxe2x80x9d means the xe2x80x94NH2 group.
The term xe2x80x9chaloalkylxe2x80x9d means a halogen linked through an alkylene group, wherein halogen and alkylene are as defined above. Illustrative examples of haloalkyl include trifluoromethyl, difluoromethyl, fluoromethyl, and 2,2,2-trichloroethyl.
The term xe2x80x9cC(O)-alkylxe2x80x9d means an alkyl group as defined above linked through a carbonyl carbon atom. Illustrative examples of C(O)-alkyl groups include acetyl (i.e., C(O)CH3), 2,2-dimethylpropionyl, and dodecanoyl.
The term xe2x80x9cheterocyclenexe2x80x9d means a 4-, 5-, or 6-membered, carbon-linked, unsubstituted or substituted with, for example, alkyl, carboxylic acid, or ester, heterocyclic diradical ring, containing from 1 to 3 heteroatoms which are N, O, or S, selected from the group consisting of:
(i) 1-aza-2-cyclobutanon-3,4-diyl of formula 
(ii) a 5-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro ring having carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S;
(iii) a 5-membered oxo-substituted nonaromatic tetrahydro ring having carbon atoms and 1 or 2 heteroatoms selected from N, O, and S;
(iv) a 6-membered aromatic, nonaromatic tetrahydro, or nonaromatic hexahydro ring having carbon atoms and 1 or 2 heteroatoms, which heteroatoms are nitrogen, and
(v) a 6-membered nonaromatic oxo-substituted hexahydro ring having carbon atoms and 1 or 2 heteroatoms which are nitrogen and 0 or 1 heteroatom which is oxygen;
wherein the radical atoms of the heterocyclene are carbon atoms, and further wherein when B is a nonaromatic heterocyclene containing sulfur, said sulfur may further comprise 
Illustrative examples of 5- and 6-membered heterocyclenes include:
1) A 5-membered heterocyclic ring having one heteroatom such as, for example, the following rings: 
xe2x80x83wherein X is O, S, or Nxe2x80x94R wherein R is H or alkyl.
2) A 5-membered, substituted or unsubstituted, wherein xe2x80x9csubstitutedxe2x80x9d is defined as above, heterocyclic ring having 2 heteroatoms such as, for example, the following rings: 
xe2x80x83wherein X and R are as defined above.
3) A 5-membered heterocyclic ring having 3 heteroatoms such as, for example, the following rings: 
xe2x80x83wherein X and R are as defined above.
4) A 6-membered aromatic heterocyclic ring having 1 to 3 nitrogen atoms such as, for example, following rings: 
5) A 6-membered nonaromatic tetrahydro heterocyclic ring having 1 or 2 nitrogen atoms such as, for example, the following rings: 
xe2x80x83wherein R is independently hydrogen or alkyl;
6) A 6-membered nonaromatic hexahydro heterocyclic ring having 1 or 2 nitrogen atoms such as, for example, the following rings: 
xe2x80x83wherein R is independently hydrogen or alkyl;
7) A 5-membered oxo-substituted heterocyclic nonaromatic tetrahydro ring having 1 or 2 heteroatoms O, S, or Nxe2x80x94R such as, for example, the following rings: 
xe2x80x83wherein X and R are as defined above.
8) A 6-membered oxo-substituted hexahydro nonaromatic heterocyclic rings having 1 or 2 nitrogen atoms, and 0 or 1 heteroatoms selected from O and S, such as, for example, the following rings: 
xe2x80x83wherein R and X are as defined above.
It is to be appreciated that the above rings do not represent all possible isomers or rings that are described above by the term xe2x80x9cheterocyclenexe2x80x9d.
It is also to be appreciated that the compounds of Formula I may have chiral centers, in which case all stereoisomers thereof, both separately and as racemic and/or diastereoisomeric mixtures, are included.
Some of the compounds of Formula I are capable of further forming nontoxic pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.
For example, pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M., et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of basic invention compounds are prepared by contacting the free base form of the invention compounds with a sufficient amount of the desired acid to produce the salt in the conventional manner.
Pharmaceutically acceptable base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).
Base salts of acidic invention compounds are prepared by contacting the free acid form of the invention compounds with a sufficient amount of the desired base to produce a salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the invention may be prepared by a number of methods well known to a person of average skill in the arts of organic and medicinal chemistries.
It should be appreciated that the organic and medicinal chemistry arts provide the skilled artisan with electronically searchable literature, reaction, and reagent databases and a wide variety of commercially available starting materials. For example, see the databases of the Chemical Abstracts service (Columbus, Ohio); Katritzky, Alan R., Handbook of Heterocyclic Chemistry, Pergamon Press, Ltd., 1985, Volumes 4 and 5; and The Aldrich Catalog (Sigma-Aldrich Corporation, St. Louis, Mo.).
For examples of the preparation of optically pure xcex942-isoxazolines (i.e., chiral xcex942-isoxazolines that consist of only one enantiomer, or substantially one enantiomer), see Yang, K-S, et al., Tetrahedron Letters, 2000;41:1453-1456 or Shimizu, M. et al., Chemistry Letters, 1996:455-456.
As described above, some of the invention compounds possess chiral centers. It should be appreciated that a person skilled in the medicinal and organic chemistry arts is able to prepare chiral invention compounds by classical resolution techniques and/or asymmetric synthesis.
It should also be appreciated for purposes of synthesizing the compounds of the invention that reactive functional groups present in starting materials, reaction intermediates, or reaction products may be protected during chemical reactions using protecting groups which render the reactive functional groups substantially inert to the reaction conditions (see for example, Protective Groups in Organic Synthesis, 2nd ed., Green T W and Wuts P G, John Wiley and Sons, New York, N.Y. 1991). Thus, for example, protecting groups such as the following may be utilized to protect suitable amino, hydroxyl, and other groups of related reactivity: carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC), xcex2,xcex2,xcex2-trichloroethoxycarbonyl (TCEC), xcex2-iodoethoxycarbonyl; aryloxycarbonyl groups, such as benzyloxycarbonyl (CBZ), p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, such as trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized. The protecting group may be removed, after completion of the synthetic reaction of interest, by procedures known to those skilled in the art. For example, a BOC group may be removed by acidolysis, a trityl group by hydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC by treatment with zinc. Use of protecting groups in organic synthesis is well within the skill of the average artisan.
It should be appreciated that reagents, solvents, and starting materials necessary for the preparation of the compounds of the invention may be purchased from a number of commercial sources or may be readily prepared by a number of methods well known to one of average skill in the art of organic chemistry. Further, reactions used to prepare the invention compounds can be carried out under a wide variety of conditions comprising solvents, reagents, catalysts, temperatures, time, atmosphere, and pressure.
Many different methods may be used to prepare the invention compounds. However for purposes of practicing the invention, which comprises compounds, pharmaceutical compositions, and methods of treating certain disorders and diseases, it does not matter how the compounds are made. Nevertheless, novel methods of preparing the invention compounds are valuable as they may afford improvements in ease of synthesis or purification, cost of preparation, or process time. As discussed above, the invention provides novel methods of making the invention compounds.
For example, one method of preparing the compounds of the invention is described below in Scheme 1. 
wherein R1, g, Z, h, R2, R3, V, B, X1, d, E, and Y are as defined above and L is a leaving group such that when V is (CH2)n or (CH2)mxe2x80x94Cxe2x95x90O, wherein m is not 0, L is, for example, halogen, CH3CO2xe2x80x94, CF3CO2xe2x80x94, CF3SO3xe2x80x94, p-toluyl-SO3xe2x80x94, and the like; and when V is Cxe2x95x90O, L is, for example, halogen, hydroxy, which can form intermediates activated for displacement by a compound of formula A by reaction with coupling agents such as, for example, carbonyldiimidazole (CDI), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), and the like, benzotriazol-1-yl, imidazol-1-yl, CH3CO2xe2x80x94, and the like.
In Scheme 1, a compound of formula A, wherein R1, g, and R2 are as defined above, is allowed to react with a compound of formula B, wherein L is a leaving group which is displaced by a compound of formula A, to provide a compound of Formula I. In a preferred procedure, a compound of formula A is dissolved or suspended in an aprotic, polar solvent such as, for example, N,N-dimethylformamide (DMF), ethyl acetate, dimethylsulfoxide (DMSO), acetonitrile, nitromethane, acetone, and the like, and optionally a 1 to 2 molar equivalents of a non-nucleophilic base such as, for example, triethylamine, diisopropylethylamine, sodium hydride, and the like is added, followed by addition of a compound of formula B as a neat material (i.e., only the material itself in solid or liquid form) or in a solution of an aprotic, polar solvent such as, for example, the aprotic, polar solvents recited above, at an addition rate that maintains a desired reaction temperature, and the mixture is stirred in air or under an inert atmosphere such as, for example, nitrogen or argon, to give a compound of Formula I. In another preferred procedure, a compound of formula A is dissolved or suspended in an aprotic, nonpolar solvent such as, for example, tetrahydrofuran (THF), diethylether, hexanes, and the like, and about one molar equivalent of a strong base such as, for example, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, potassium hexamethyldisilazide (KHMDS), and the like is added, followed by addition of a compound of formula B as a neat material or in a solution of a nonpolar, aprotic solvent such as, for example, the nonpolar, aprotic solvents recited above, at an addition rate that maintains a desired reaction temperature, and the mixture is stirred to give a compound of Formula I. In still another preferred procedure, a compound of formula B, wherein Lxe2x80x94Vxe2x80x94 is HOxe2x80x94C(O)xe2x80x94, is dissolved or suspended in an aprotic solvent such as, for example, THF, DMF, ethyl acetate, and the like, and about 1 molar equivalent of a coupling agent such as, for example, CDI, DCC, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPxe2x80x94Cl), and the like, followed by addition of a compound of formula A as a neat material or in a solution of an aprotic solvent such as, for example, the aprotic solvents recited above, at an addition rate that maintains a desired reaction temperature, and the mixture is stirred to give a compound of Formula I. In Scheme 1, the preferred molar ratio of a compound of formula A to a compound of formula B is about 1:1.
Another method of preparing the compounds of the invention is described below in Scheme 2. 
wherein Rl, g, Z, h, R2, R3, V, B, X1, d, E, and Y are as defined above, and PG1 and PG2 are protecting groups which may be deprotected to provide the groups E and Y, respectively, of compounds of Formula I. Illustrative examples of PG1 are hydrogen (when E is H), xe2x80x94O-benzyl, xe2x80x94S-benzyl, xe2x80x94NH-benzyl, xe2x80x94NH-(4-methoxybenzyl), xe2x80x94NHxe2x80x94BOC, xe2x80x94NHxe2x80x94CBZ, xe2x80x94Oxe2x80x94TBDMS, xe2x80x94CH2-halo, C(O)xe2x80x94CH2-halo, xe2x80x94CO2Me, C(Oxe2x80x94CH2)2, CH2CH2CO2Me, and the like. Illustrative examples of PG2 are xe2x80x94NH-benzyl, xe2x80x94NH-(4-methoxybenzyl), xe2x80x94NHxe2x80x94BOC, xe2x80x94NHxe2x80x94CBZ, CO2Me, xe2x80x94O-benzyl, xe2x80x94Oxe2x80x94TBDMS, and the like.
In Scheme 2, a compound of formula C is deprotected to give a compound of Formula I. In a preferred procedure, a compound of formula C, wherein PG1 and/or PG2 is xe2x80x94O-benzyl, xe2x80x94S-benzyl, xe2x80x94NH-benzyl, xe2x80x94NHxe2x80x94CBZ, and the like, is dissolved or suspended in a suitable solvent such as, for example, acetic acid, ethanol, THF, dichloromethane, and the like, and allowed to react with a deprotecting reagent such as, for example, a mixture of hydrogen gas and a suitable hydrogenation catalyst such as, for example, palladium on carbon, palladium on barium sulfate, platinum on carbon, sponge nickel, and the like, under pressure, phosphorous tribromide, hydrochloric acid, titanium tetrachloride, and the like, at an addition rate that maintains a desired reaction temperature, to give a compound of Formula I. Examples 1, 3, 4a, 4b, 5, and 9 are representative of the chemistry described in Scheme 2.
Another method of preparing the compounds of the invention is described below in Scheme 3. 
wherein R1, g, Z, h, R2, R3, V, B, X1, d, E, and Y are as defined above, and U is xe2x80x94C(H)xe2x95x90C(H)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94.
In Scheme 3, a compound of formula D is allowed to react with a 3- or 4-membered cyclization reagent to give a compound of Formula I, wherein B is a 5- or 6-membered heterocyclene, respectively. In a preferred procedure, a compound of formula D is dissolved or suspended in an aprotic solvent such as, for example, THF, dichloromethane, acetone, DMF, and the like, and allowed to react with a 3-membered cyclizing reagent such as, for example, an alkylazide, alkyldiazomethane, acetonitrile oxide, prepared by reaction of an aldoxime such as, for example, acetaldoxime [i.e., CH3C(H)xe2x95x90Nxe2x80x94OH] with a radical generating agent such as, N-bromosuccinimide (NBS), N-chlorosuccinimde (NCS), and the like, or a 4-membered cyclizing reagent such as, for example, H2Cxe2x95x90C(H)xe2x80x94C(H)xe2x95x90Nxe2x80x94EDG, wherein EDG is an electron donating group such as, for example, xe2x80x94N(CH3)2, xe2x80x94OMe, and the like, to give a compound of Formula I. Example 2 is representative of the chemistry described in Scheme 3.
Another method of preparing the compounds of the invention is described below in Scheme 4. 
wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above, B is oxazole, dihydrooxazole, thiazole, or dihydrothiazole, and T is Cxe2x95x90O or C(H)OH.
In Scheme 4, a compound of formula E is allowed to react with a reagent and/or catalyst under cyclizing conditions to provide a compound of Formula I. In a preferred procedure, a compound of formula D is dissolved in an aprotic solvent such as, for example, THF, ethyl acetate, DMF, DMSO, and the like, and a dehyrdating reagent such as, for example, anhydrous magnesium sulfate, anhydrous calcium chloride, activated 3 angstrom molecular sieves, trimethoxymethane, oxalyl chloride, PCl5, phosphorous pentoxide and the like, is added and optionally an acid catalyst such as, for example, trifluoroacetic acid, para-toluenesulfonic acid, and the like, is added, and the mixture is stirred to provide a compound of Formula I, wherein B is oxazole or dihydrooxazole. In another preferred procedure, a compound of formula D is dissolved in an aprotic solvent such as, for example, THF, ethyl acetate, DMF, DMSO, and the like, and a sulfurating reagent (i.e., a reagent that introduces a sulfur atom) such as, for example, P2S5, [2,4-bis(4-methoxyphenyl)-1,3-dithian-2,4-diphosphetane-2,4-disulfide] (i.e., Lawesson""s reagent), and the like, is added, and the mixture is stirred to provide a compound of Formula I, wherein B is thiazole or dihydrothiazole. Examples 6(a)-6(f) and 8 are representative of the chemistry described in Scheme 4.
Another method of preparing the compounds of the invention is described below in Scheme 5. 
wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above, B is oxazole, dihydrooxazole, thiazole, or dihydrothiazole, and T is Cxe2x95x90O or C(H)OH.
In Scheme 5, a compound of Formula F is allowed to react with a reagent and/or catalyst under cyclizing conditions to provide a compound of Formula I. Preferred procedures are as described above in Scheme 4. Examples 7(a) and 7(b) are representative of the chemistry described in Scheme 5.
Another method of preparing the compounds of the invention is described below in Scheme 6. 
wherein R1, g, Z, h, R2, R3, V, B, X1, d, E, and Y are as defined above.
In Scheme 6, a compound of Formula I is allowed to react with a reagent to provide a different compound of Formula I. In a preferred procedure, a compound of Formula I wherein V is (CH2)mCxe2x95x90O is dissolved or suspended in a suitable aprotic, nonpolar solvent such as, for example, THF, methyl-tert-butylether (MTBE), hexanes, and the like, and a reducing agent such as, for example, lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride (DIBAL), and the like, is added at an addition rate that maintains a desired reaction temperature, and the mixture is stirred to give a compound of Formula I wherein V is (CH2)n.
Another method of preparing the compounds of the invention is described below in Scheme 7. 
wherein R1, g, Z, h, R2, R3, V, X1, d, E, and Y are as defined above, B is isoxazole, dihydroisoxazole (i.e., isoxazoline), dihydrothiazoline, or oxazole; J is C(H)xe2x95x90CH2 or Cxe2x89xa1Cxe2x80x94H, and K is C(Cl)xe2x95x90Nxe2x80x94OH.
In Scheme 7, a compound of formula G is allowed to react with a compound of formula H under [3+2] cyclization conditions to provide a compound of formula I. In a preferred procedure, a compound of formula G and a compound of formula H are dissolved or suspended in a solvent such as, for example, methanol, ethanol, THF, ethyl acetate, toluene, dichloromethane, and the like, and optionally a non-nucleophilic base such as, for example, triethylamine, diisopropylethylamine, sodium hydride, and the like is added, and the mixture is stirred to provide a compound of Formula I. Examples 10 to 16 are representative of the chemistry described in Scheme 7.
Examples of the preparation of the invention compounds are described below.